We developed a series of compounds that show excellent in vivo antimalarial efficacy in mouse models against blood-, liver and transmission-stage parasites. We demonstrated that these compounds act via a novel mechanism-of-action (inhibition of P. falciparum cytosolic phenylalanyl tRNA synthetase, PfcPheRS) and as such this program represents an important development to combat antimalarial resistance. A lead compound, BRD5018, was identified that had potent in vivo efficacy and an improved safety profile relative to early lead compounds. In biochemical aminoacylation assays BRD5018 had weak inhibition of the enzymatic activity of human cPheRS while potent inhibition of PfcPheRS. We defined the API manufacturing route and prepared sufficient API to enable non-GLP nonclinical studies such as in vivo efficacy and non-rodent DRF studies. We also performed physicochemical characterization, analytical development and salt selection studies on BRD5018. A synthetic route was developed that enabled the delivery of sufficient material to support non-rodent CV and dose range finding toxicity study studies. We also developed a completely new low-cost synthetic route to BRD5018. To support toxicological studies and human dose predictions, a series of pharmacokinetic studies were conducted in rodents and dogs. Overall, the toxicity profile was consistent across preclinical species, with primary findings related to gastrointestinal (GI) toxicity likely due to local irritation and no serious systemic toxicity identified. The GI toxicity is monitorable and reversible. These studies fulfill key steps on the path to first-in-man clinical studies for BRD5018 as an antimalarial agent.